The proposed research concerns the electrophysiological and pharmacological investigations of the interactions of several neurotransmitters and neuromodulators which are released at or are present in autonomic ganglia, and the mechanisms by which the interactions of these endogenous substances modify the primary nicotinic transmission pathway as well as the secondary pathways. Three types of modulatory mechanisms have been identified, and will be investigated by intracellular and extracellular recording techniques on isolated sympathetic ganglia of the rabbit, rat, guinea pig and bullfrog. First, the intrasynaptic mechanisms which involve postsynaptic muscarinic, adrenergic, and noncholinergic receptors, generating the slow potentials, namely the slow epsp, slow ipsp, and late slow epsp, respectively, will be investigated. The studies of the role of cyclic nucleotides in the generation or modulation of the slow synaptic potentials will be continued. Second, the intersynaptic mechanisms will be evaluated; these mechanisms may involve two major components, the small intensely fluorescent (SIF) cells and inter-neuronal connections. The nature of response and the transmitter responsible for the inter-neuronal communication between principal neurons, as well as SIF cells and principal neurons will be explored. The third type of modulatory influence concerns endogenous peptides and other endogenous substances, such as DA and serotonin. The site and ionic mechanism of actions of these substances will be studied.